Insight into male menopause' Dr Mark Vanderpump MD FRCP Consultant Endocrinologist Clinics: Tuesday PM
Mark Vanderpump Consultant Physician and Endocrinologist
Introduction Serum total and free testosterone decrease with age Decline known as andropause or late-onset hypogonadism Complete oestrogen deficiency syndrome known in women Decline in testosterone in ageing men is modest and possible clinical consequences not been well-established. Changes in body function in ageing men similar to manifestations of hypogonadism Does decline in testosterone with ageing cause these changes? Prescriptions for testosterone preparations increased by 90% to 300,000 dispensed items annually over 10 years NHS costs 267% rose from 3 2 to 11 7 million/year 2000-10
Objectives Testosterone levels in the ageing man Which tests to do and when Diagnosis of hypogonadism in the ageing man Who should be treated? How should you treat?
Cases Case 1 59 year old married CEO c/o loss of libido, poor erections, hot flushes Hypertension on Amlodipine. On statin. HbA1c 43mmol/mol BMI 31Kg/m 2, waist circumference 42 inches Checked testosterone level at BUPA medical 9.9nmol/L Convinced that has menopause and requests Testosterone Case 2 62 year old teacher c/o low energy, myalgia post exercise, difficulty with memory. PMH Crohn s disease on Azathioprine BMI 26Kg/m2, waist circumference 36 inches Recent fracture elbow post fall, BMD T score osteopaenic range Recommended to have testosterone checked by orthopaedic surgeon Testosterone 7.8nmol/L
Physiology
Measurement of testosterone What form (total or free), when during the day, and how often should serum testosterone be measured? Obesity decreases total testosterone concentration usually without lowering the free testosterone concentration Severe obesity (BMI >40kg/m 2 ) may cause hypothalamic hypogonadism as well as the binding abnormality Equilibrium dialysis (not analogue method) will distinguish a binding abnormality and hypogonadism in an obese male Free testosterone concentration from total testosterone, SHBG, and albumin concentrations, may also be reliable Harmonised reference range of total testosterone in 9000 non-obese European/US men is 9.2-31.8nmol/L
Evaluation of possible hypogonadism
Relationship between age and hormones
Diurnal rhythm of testosterone secretion
Relationship between hormones and BMI
Serum testosterone levels in obesity
Lowered testosterone levels in obesity
Consequences of testosterone decline Sexual function: In 3369 men ages 40-79 years (European Male Aging Study) only symptoms significantly associated with serum testosterone <11.1nmol/L were three sexual symptoms (poor morning erection, low sexual desire, and erectile dysfunction) Bone mineral density and fractures: In men >65 years, the risk of non-vertebral fractures was increased in those with low bioavailable oestradiol and testosterone and high SHBG. Muscle and fat mass: Hypogonadal men have less muscle mass and more fat mass than normal men; testosterone treatment tends to reverse these changes
Consequences of testosterone decline Anaemia: In placebo-controlled trials in older men, testosterone treatment results in increase in haemoglobin when compared with placebo, but correction of anaemia not been demonstrated Mood: Associated with depressive symptoms, even after correction for possible confounders. In hypogonadal men, raising testosterone concentration improved mood Cognitive function: Decline in neuropsychological function Metabolic cardiovascular parameters: Associated with development of central obesity, higher insulin concentrations, the metabolic syndrome, type 2 diabetes, high CRP and increased mortality
Does late-onset hypogonadism exist? European Male Aging Study (EMAS) described 3369 men aged 40-79 with low testosterone for no reason other than age Low testosterone (<11nmol/L) and three sexual symptoms (in 2.1% of men) significantly associated with lower Hb, heel BMD, mid-upper arm circumference, and physical performance More severe hypogonadism (serum testosterone concentration <8nmol/L) was also associated with insulin resistance Associations were stronger when serum testosterone concentration was <8nmol/L than when 8-11nmol/L range These data support the concept of low testosterone syndrome in small % of middle aged and older men
Clinical trial data Testosterone for three years did not increase BMD in spine or hip compared with placebo, but secondary analysis showed that the lower the pre-treatment testosterone, the greater the testosterone treatment effect on spine BMD Testosterone for 1 year did not increase spine BMD compared with placebo but prevented a decrease in hip BMD Study in which testosterone raised to higher than mid-normal treatment significantly increased BMD 10% spine and 2.5% hip Meta-analysis of 8 trials of 365 patients concluded that trials of im testosterone esters showed a modest improvement in spine (but not femoral neck) BMD, but not transdermal testosterone
Clinical trial data Body composition: Increase in lean body mass (2.7 kg) and a greater reduction in fat mass (-2.0 kg) than placebo Muscle strength: Increase in lean mass not accompanied by increases in muscle strength Physical function: No improvement in various parameters of physical function in two trials, but in the third was associated with increase in composite physical performance test Quality of life: In meta-analysis of 17 trials, those that enrolled subjects with low testosterone showed a large effect on libido, but little or no effect on erectile function and sexual satisfaction Mood: Two small RCTs showed benefit on mood
Men > 65 years (n = 790). Low serum testosterone <9.54nmol/L on two occasions Symptoms and objective evidence of sexual dysfunction, physical dysfunction, and reduced vitality were randomly assigned to receive testosterone or placebo gel for one year and participated in three main trials (the Sexual Function, Physical Function, and Vitality trials). Over 51,000 men screened to enroll the 790 men who met inclusion criteria (only 1.5% of those screened had low serum testosterone and hypogonadal symptoms). After 1 year of testosterone gel therapy, serum testosterone concentrations increased into the mid-normal range for men ages 19-40 years
The Testosterone Trials (NEJM 2016) Increases in sexual activity and desire, and erectile function No significant difference in walking distance on six-minute walk test in the Physical Function trial (but differences were seen when subjects from all three trials were included) No significant benefit on vitality, however, men receiving testosterone reported better mood and lower severity of depressive symptoms when compared with placebo Rates of adverse events similar with testosterone and placebo The risk of cardiovascular complications could not be assessed given the size and duration of the trial
Potential harmful effects Prostate cancer: Meta-analysis of 51 randomised trials no increased incidence, need for prostate biopsy, or other prostate outcomes Benign prostatic hyperplasia: No effect on lower urinary tract symptoms or other prostate outcomes Sleep apnoea: Physiological replacement increases sleep apnoea but meta-analysis showed no difference Erythrocytosis: In study of 45 men (age 72 years) im testosterone increased haematocrit to >52% in 24%. In Framingham men in highest quintile haematocrit had greater overall mortality and cardiovascular mortality Serum lipids: No effect
Potential harmful effects FDA issued alerts re potential concerns about testosterone therapy and cardiovascular safety Despite conflicting and inconclusive evidence, there is possibility of increased cardiovascular risk (MI and CVA) Retrospective studies limited by inability to verify diagnoses, indications for testosterone therapy, testosterone dose, and information on serum testosterone concentrations immediately before initiating therapy and during therapy IM preparations associated with a greater risk of MI and stroke but not VTE when compared with testosterone gel
Testosterone treatment Testosterone metabolised so rapidly by liver that impossible to maintain normal serum testosterone with oral testosterone Testosterone gels typically result in normal and relatively stable serum testosterone concentrations Other factors affect choice of regimen, including patient preference, cost, convenience Gels cost the most, the patch costs somewhat less, and injectable esters cost the least. Testosterone undecanoate (Nebido) as 1g deep IM injection, with a second dose six weeks after the first and subsequent doses every 10-14 weeks
NHS advice
What do I do? Measure fasting total testosterone x2 Repeat with SHBG, LH, FSH and Prolactin Assess free testosterone level with SHBG FT4, TSH, Cortisol, MRI pituitary, Ferritin Look for other clinical features of insulin resistance Bone density useful at baseline Check baseline FBC, PSA Offer Testosterone gel trial for 3 months Symptom improvement 3 months, BMD 2 years Switch to Nebido if preferred as long-term treatment Six monthly check of FBC/PSA Agree definition of successful clinical outcome
Conclusion Late-onset hypogonadism occurs in 2% ageing males Level that considered unequivocally low are <7nmol/L Confirmed if <7-9nmol/L x2 early am with estimation of free testosterone with SHBG and pituitary pathology excluded Sexual symptoms are loss of libido and erectile dysfunction Offer replacement therapy to those with testosterone deficiency symptoms and testosterone (<7-9nmol/L) Individualised evaluation of co-morbidities and risk-benefit Safety profile appears good but evidence from large randomised prospective trials of beneficial effects and cardiovascular safety of testosterone therapy needed
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